Employing a 1980 Hawaii recollection of Pancratium (later reassigned Hymenocallis) littorale bulbs a very potent anticancer constituent was located. In 1984 the isolation (0.028% yield) and structure (by x-ray of the 7-meth-oxy derivative) of this important substance designated (+)-pancratistatin (1a). (See: Mohammad, R. M.; Limvarapuss, C.; Wall, N. R.; Hamdy, N.; Beck, F. W. J.; Pettit, G. R.; Al-Katib, A. Int. J. Oncology 1999, 15, 367-372). Subsequently, the U.S. National Cancer Institute initiated preclinical development of pancratistatin due to its high level of vitro and in vivo cancer cell growth inhibitory (including antiviral) (See: Gabrielsen, B.; Monath, T. P.; Huggins, J. W.; Kevauver, D. F.; Pettit, G. R.; Groszek, G.; Holingshead, M.; Kirsi, J. J.; Shannon, W. M.; Schubert, E. M.; DaRe, J.; Ugarkar, B.; Ussery, M. A.; Phelan, M. J. J. Nat. Prod. 1992, 55, 1569-1581; and (b) Gabrielsen, B.; Monath, T. P.; Huggins, J. W.; Kirsi, J. J.; Holingshead, M.; Shannon, W. M.; Pettit, G. R. In Natural Products as Antiviral Agents; Chu, C. K., Cutler, H. G., Eds.; Plenum: New York, 1992; pp 121-135) activity. Unfortunately, the preclinical development of this potentially important anticancer drug has been slowed by severe supply constraints and by its very low aqueous solubility (53 g/ml) properties. (See: Torres-Labaneira, J. J.; Davignon, P.; Pitha, J. J. Pharm. Sci. 1991, 80, 384-386). The latter problem was finally solved to a degree by the conversion of (+)-pancratistatin (1a) to a water soluble (>230 mg/ml) and comparably active phosphate (1b) prodrug (See: Pettit, G. R.; Freeman, S.; Simpson, M. J.; Thompson, M. A.; Boyd, M. R.; Williams, M. D.; Pettit, G. R. III; Doubek, D. L. Anti-Cancer Drug Design 1995, 10, 243-250). In addition, supplies of (+)-pancratistatin have been gradually increased by cloning and growing the plant in Arizona (See: Pettit, G. R.; Pettit, G. R. III; Groszek, G.; Backhaus, R. A.; Doubek, D. L.; Barr, R. J.; Meerow, A. W. J. Nat. Prod. 1995, 58, 756-759). However, a very efficient and commercially viable synthesis of this deceptively simple isocarbostyril is still needed and would be especially useful.
Considerable research efforts (See: Hoshino, O. The Alkaloids; Cordell, G. A. Ed.; Academic Press: vol. 51; San Diego, 1998; pp. 323) have been devoted to developing a practical synthesis of pancratistatin (1a). Four of these have led to pancratistatin. The first synthesis (See: Danishefsky, S.; Lee, J. Y. J. Am. Chem. Soc. 1989, 111, 4829-4837) provided racemic pancratistatin in 26 steps with an overall yield of 0.13%. The first enantioselective synthesis in 14 steps from bromobenzene (2% overall yield) of (+)-pancratistatin was reported by (See: Tian, X.; Hudlicky, T.; Königsberger, K. J. Am. Chem. Soc. 1995, 117, 3643-3644), in 1995. The same year, (See: Trost, B. M.; Pulley, S. R. J. Am. Chem. Soc. 1995, 117, 10143-10144) summarized a syntheses with an impressive 11% overall yield utilizing 13 steps. More recently, (See: Doyle, T. J.; Hendrix, M. M.; Van Der Veer, D.; Jaanmard, S.; Haseltine, J. Tetrahedron 1997, 53, 11153-11170) and (See: Magnus, P.; Sebhat, I. K. Tetrahedron 1998, 54, 15509-15524) (22 steps, 1.2% yield) have presented new synthesis of (+)-pancratistatin: In addition, a new synthesis of 7-deoxypancratistatin (1c) has been completed (13 steps, 21% overall yield) (See: Keck, G. E.; Wager, T. T-S; McHardy, S. F.; J. Org. Chem. 1998, 63, 9164-9165) and other new approaches to lactones 1a are in progress (See: Grubb, L. M.; Dowdy, A. L.; Blanchette, H. S.; Friestad, G. K.; Branchaud, B. P. Tetrahedron Lett. 1999, 40, 2691-2694; Aceña, J. L.; Arjona, O.; Iradier, F.; Plumet, J. Tetrahedron Lett. 1996, 37, 105-106; Gauthier, D. R.; Bender, S. L. Tetrahedron Lett. 1996, 37, 13-16).
From the beginning, the efforts to synthesize pancratistatin (1a) has focused on narciclasine (See: Ceriotti, G. Nature 1967, 213, 595-596; Okamoto, T.; Torii, Y.; Isogai, Y. Chem. Pharm. Bull. 1968, 24, 1119-1131; Mondon, A.; Krohn, K. Chem. Ber. 1975, 108, 445-463) (2) as the most attractive precursor, because it is available in practical quantities from the bulbs of certain Amaryllidaceae species. It has been studied in some detail (See: Rigby, J. H.; Mateo, M. E. J. Am. Chem. Soc. 1997, 119, 12655-12.656; Banwell, M. G.; Cowden, C. J.; Gable, R. W. J. Chem. Soc. Perkin Trans. 1 1994, 3515-3518; and Krohn, K; Mondon, A. Chem. Ber. 1976, 109, 855-876; Banwell, M. G.; Cowden, C. J.; Mackey, M. F. J. Chem. Soc., Chem. Commun. 1994, 61-62; Khaldi, M.; Chretien, F.; Chapleur, Y. Tetrahedron Lett. 1995, 36, 3003-3006; Park, T. K.; Danishefsky, S. J. Tetrahedron Lett. 1995, 36, 195-196; Angle, S. R.; Wada, T. Tetrahedron Lett. 1997, 38 7955-7958) leading to its recent synthesis in twelve steps by Hudlicky, starting from an enzymatic dihydroxylation of m-dibromo benzene (See: Gonzalez, D.; Martinot, T.; Hudlicky, T. Tetrahedron Lett. 1999, 40, 3077-3080). Earlier, the Cancer Research Institute at Arizona State University attempted to develop a practical synthesis of pancratistatin from narciclasine (2) and easily obtained 10b-R-hydroxy-pancratistatin (See: Pettit, G. R; Melody, N.; O'Sullivan, M.; Thompson, M.; Herald, D. L.; Coates, B. J. Chem. Soc., Chem. Commun. 1994, 2725-2726). But the last step, namely, the hydrogenolysis of the benzyl alcohol did not lead to (+)-pancratistatin. Through continuing effort, however, a successful synthesis of (+)-pancratistatin (1a) from (+)-narciclasine (2) in 3.6% overall yield has now been developed and that development forms the basis of this disclosure.
Attention is also directed to Dr. Pettit's earlier U.S. Pat. Nos. 4,866,071; 4,985,436; and 5,529,989 and particularly the background disclosed therein which is incorporated herein by this reference thereto.